tbuckley/cabot-search huggingface dataset:
Cytosolic TGM2 promotes malignant progression in gastric cancer by suppressing the TRIM21‐mediated ubiquitination/degradation of STAT1 in a GTP binding‐dependent modality
Authors: Lu Zhang, Qingya Li, Jing Yang, Penghui Xu, Zhe Xuan, Jianghao Xu, Zekuan Xu
Journal: Cancer Communications (2022)

Previous studies have revealed the critical role of transglutaminase 2 (TGM2) as a potential therapeutic target in cancers, but the oncogenic roles and underlying mechanisms of TGM2 in gastric cancer (GC) are not fully understood. In this study, we examined the role and potential mechanism of TGM2 in GC.Western blotting, immunohistochemistry, CCK8, colony formation and transwell assays were used to measure TGM2 expression in the GC cells and tissues and to examine the in vitro role of TGM2 in GC. Xenograft and in vivo metastasis experiments were performed to examine the in vivo role of TGM2 in GC. Gene set enrichment analysis, quantitative PCR and western blotting were conducted to screen for potential TGM2 targets involved in GC. Gain/loss-of-function and rescue experiments were conducted to detect the biological roles of STAT1 in GC cells in the context of TGM2. Co-immunoprecipitation, mass spectrometry, quantitative PCR and western blotting were conducted to identify STAT1-interacting proteins and elucidate their regulatory mechanisms. Mutations in TGM2 and two molecules (ZM39923 and A23187) were used to identify the enzymatic activity of TGM2 involved in the malignant progression of GC and elucidate the underlying mechanism.In this study, we demonstrated elevated TGM2 expression in the GC tissues, which closely related to pathological grade, and predicted poor survival in patients with GC. TGM2 overexpression or knockdown promoted (and inhibited) cell proliferation, migration, and invasion, which were reversed by STAT1 knockdown or overexpression. Further studies showed that TGM2 promoted GC progression by inhibiting STAT1 ubiquitination/degradation. Then, tripartite motif-containing protein 21 (TRIM21) was identified as a ubiquitin E3 ligase of STAT1 in GC. TGM2 maintained STAT1 stability by facilitating the dissociation of TRIM21 and STAT1 with GTP-binding enzymatic activity. A23187 abolished the role of TGM2 in STAT1 and reversed the pro-tumor role of TGM2 in vitro and in vivo.This study revealed a critical role and regulatory mechanism of TGM2 on STAT1 in GC and highlighted the potential of TGM2 as a therapeutic target, which elucidates the development of medicine or strategies by regulating the GTP-binding activity of TGM2 in GC.
Artificial Intelligence You Can Trust: What Matters Beyond Performance When Applying Artificial Intelligence to Renal Histopathology?
Authors: John O.O. Ayorinde, Federica Citterio, Matteo Landrò, Elia Peruzzo, Tuba Islam, Simon Tilley, Geoffrey Taylor, Victoria Bardsley, Pietro Liò, Alex Samoshkin, Gavin J. Pettigrew
Journal: Journal of the American Society of Nephrology (2022)

Although still in its infancy, artificial intelligence (AI) analysis of kidney biopsy images is anticipated to become an integral aspect of renal histopathology. As these systems are developed, the focus will understandably be on developing ever more accurate models, but successful translation to the clinic will also depend upon other characteristics of the system. In the extreme, deployment of highly performant but “black box” AI is fraught with risk, and high-profile errors could damage future trust in the technology. Furthermore, a major factor determining whether new systems are adopted in clinical settings is whether they are “trusted” by clinicians. Key to unlocking trust will be designing platforms optimized for intuitive human-AI interactions and ensuring that, where judgment is required to resolve ambiguous areas of assessment, the workings of the AI image classifier are understandable to the human observer. Therefore, determining the optimal design for AI systems depends on factors beyond performance, with considerations of goals, interpretability, and safety constraining many design and engineering choices. In this article, we explore challenges that arise in the application of AI to renal histopathology, and consider areas where choices around model architecture, training strategy, and workflow design may be influenced by factors beyond the final performance metrics of the system.
Design and Preclinical Evaluation of a Novel B7-H4–Directed Antibody–Drug Conjugate, AZD8205, Alone and in Combination with the PARP1-Selective Inhibitor AZD5305
Authors: Krista Kinneer, Philipp Wortmann, Zachary A. Cooper, Niall J. Dickinson, Luke Masterson, Thais Cailleau, Ian Hutchinson, Balakumar Vijayakrishnan, Mary McFarlane, Kathryn Ball, Michael Davies, Arthur Lewis, Yue Huang, Anton I. Rosenbaum, Jiaqi Yuan, Jon Chesebrough, Judith Anderton, Noel Monks, Steven Novick, Jixin Wang, Nazzareno Dimasi, R. James Christie, Darrin Sabol, Frances Anne Tosto, Yann Wallez, Elisabetta Leo, Mark R. Albertella, Anna D. Staniszewska, David A. Tice, Philip W. Howard, Nadia Luheshi, Puja Sapra
Journal: Clinical Cancer Research (2022)

Abstract Purpose: We evaluated the activity of AZD8205, a B7-H4–directed antibody–drug conjugate (ADC) bearing a novel topoisomerase I inhibitor (TOP1i) payload, alone and in combination with the PARP1-selective inhibitor AZD5305, in preclinical models. Experimental Design: IHC and deep-learning–based image analysis algorithms were used to assess prevalence and intratumoral heterogeneity of B7-H4 expression in human tumors. Several TOP1i-ADCs, prepared with Val-Ala or Gly–Gly–Phe–Gly peptide linkers, with or without a PEG8 spacer, were compared in biophysical, in vivo efficacy, and rat toxicology studies. AZD8205 mechanism of action and efficacy studies were conducted in human cancer cell line and patient-derived xenograft (PDX) models. Results: Evaluation of IHC-staining density on a per-cell basis revealed a range of heterogeneous B7-H4 expression across patient tumors. This informed selection of bystander-capable Val-Ala–PEG8–TOP1i payload AZ14170133 and development of AZD8205, which demonstrated improved stability, efficacy, and safety compared with other linker–payload ADCs. In a study of 26 PDX tumors, single administration of 3.5 mg/kg AZD8205 provided a 69% overall response rate, according to modified RECIST criteria, which correlated with homologous recombination repair (HRR) deficiency (HRD) and elevated levels of B7-H4 in HRR-proficient models. Addition of AZD5305 sensitized very low B7-H4–expressing tumors to AZD8205 treatment, independent of HRD status and in models representing clinically relevant mechanisms of PARPi resistance. Conclusions: These data provide evidence for the potential utility of AZD8205 for treatment of B7-H4–expressing tumors and support the rationale for an ongoing phase 1 clinical study (NCT05123482). See related commentary by Pommier and Thomas, p. 991
Genome-Wide Analysis of Rare Haplotypes Associated with Breast Cancer Risk
Authors: Fan Wang, Wonjong Moon, William Letsou, Yadav Sapkota, Zhaoming Wang, Cindy Im, Jessica L. Baedke, Leslie Robison, Yutaka Yasui
Journal: Cancer Research (2022)

Abstract Numerous common genetic variants have been linked to breast cancer risk, but they only partially explain the total breast cancer heritability. Inference from Nordic population-based twin data indicates rare high-risk loci as the chief determinant of breast cancer risk. Here, we use haplotypes, rather than single variants, to identify rare high-risk loci for breast cancer. With computationally phased genotypes from 181,034 white British women in the UK Biobank, a genome-wide haplotype–breast cancer association analysis was conducted using sliding windows of 5 to 500 consecutive array-genotyped variants. In the discovery stage, haplotype–breast cancer associations were evaluated retrospectively in the prestudy-enrollment data including 5,487 breast cancer cases. Breast cancer hazard ratios (HR) for additive haplotypic effects were estimated using Cox regression. The replication analysis included a prospective cohort of women free of breast cancer at enrollment, of whom 3,524 later developed breast cancer. This two-stage analysis detected 13 rare loci (frequency &amp;lt;1%), each associated with an appreciable breast cancer-risk increase (discovery: HRs = 2.84–6.10, P &amp;lt; 5 × 10–8; replication: HRs = 2.08–5.61, P &amp;lt; 0.01). In contrast, the variants that formed these rare haplotypes individually exhibited much smaller effects. Functional annotation revealed extensive cis-regulatory DNA elements in breast cancer–related cells underlying the replicated rare haplotypes. Using phased, imputed genotypes from 30,064 cases and 25,282 controls in the DRIVE OncoArray case–control study, 6 of the 13 rare–loci associations were found generalizable (odds ratio estimates: 1.48–7.67, P &amp;lt; 0.05). This study demonstrates the complementary advantage of utilizing rare haplotypes to capture novel risk loci and suggests the potential for the discovery of more genetic elements contributing to cancer heritability as large data sets of germline whole-genome sequencing become available. Significance: A genome-wide two-stage haplotype analysis identifies rare haplotypes associated with breast cancer risk and suggests that the rare risk haplotypes represent long-range interactions with regulatory consequences influencing cancer risk.
Cost-effectiveness of Prostate Cancer Screening Using Magnetic Resonance Imaging or Standard Biopsy Based on the STHLM3-MRI Study
Authors: Shuang Hao, Andrea Discacciati, Martin Eklund, Emelie Heintz, Ellinor Östensson, K. Miriam Elfström, Mark S. Clements, Tobias Nordström
Journal: JAMA Oncology (2022)

Importance The combination of prostate-specific antigen (PSA) testing with magnetic resonance imaging (MRI) for prostate cancer detection has rarely been evaluated in a screening context. The STHLM3-MRI screening-by-invitation study ( NCT03377881 ) has reported the benefits of using MRI with subsequent combined targeted and standard biopsies compared with using standard biopsies alone. Objective To investigate the cost-effectiveness of prostate cancer screening using MRI with combined targeted and standard biopsies compared with standard biopsies alone among men aged 55 to 69 years in Sweden, based on evidence from the STHLM3-MRI study. Design, Setting, and Participants This economic evaluation study was conducted from a lifetime health care perspective using a microsimulation model to evaluate no screening and screening strategies among adult men in Sweden. Men aged 55 to 69 years in Sweden were simulated for no screening and screening strategies. Input parameters were obtained from the STHLM3-MRI study and recent reviews. One-way and probabilistic sensitivity analyses were performed in May 2022. Interventions No screening, quadrennial PSA screening using standard biopsies alone, and MRI-based screening using combined targeted and standard biopsies. Main Outcomes and Measures The number of tests, incidence, deaths, costs, quality-adjusted life-years (QALY), and incremental cost-effectiveness ratios (ICERs) were estimated. Results A total 603 men were randomized to the standard arm, 165 of these participants (27.4%) did not undergo standard biopsy; 929 men were randomized to the experimental arm, 111 (11.9%) of whom did undergo MRI or any biopsy. Compared with no screening, the screening strategies were associated with reduced lifetime prostate cancer–related deaths by 6% to 9%. Screening with MRI and the combined biopsies resulted in an ICER of US $53 736, which is classified as a moderate cost per QALY gained in Sweden. Relative to screening with standard biopsies alone, MRI-based screening reduced the number of both lifetime biopsies and overdiagnosis by approximately 50% and had a high probability of being cost-effective than the traditional PSA screening. Conclusions and Relevance For prostate cancer screening, this economic evaluation study found that PSA testing followed by MRI with subsequent combined targeted and standard biopsies had a high probability to be more cost-effective compared with the traditional screening pathway using PSA and standard biopsy. MRI-based screening may be considered for early detection of prostate cancer in Sweden.
Carbon Dot@MXene Nanozymes with Triple Enzyme‐Mimic Activities for Mild NIR‐II Photothermal‐Amplified Nanocatalytic Therapy
Authors: Bijiang Geng, Lang Yan, Yuping Zhu, Wenjing Shi, Haoneng Wang, Jingjing Mao, Lijun Ren, Jiqianzhu Zhang, Yijun Tian, Fangyuan Gao, Xiaofang Zhang, Jikuai Chen, Jiangbo Zhu
Journal: Advanced Healthcare Materials (2022)

Nanozymes have shown promising potential in disease treatment owing to the advantages of low-cost, facile fabrication, and high stability. However, the highly complex tumor microenvironment (TME) and inherent low catalytic activity severely restrict the clinical applications of nanozymes. Herein, a novel mild hyperthermia-enhanced nanocatalytic therapy platform based on Z-scheme heterojunction nanozymes by depositing N-doped carbon dots (CDs) onto Nb2 C nanosheets is constructed. CD@Nb2 C nanozymes not only display outstanding photothermal effects in the safe and efficient NIR-II window but also possess triple enzyme-mimic activities to obtain amplified ROS levels. The triple enzyme-mimic activities and NIR-II photothermal properties of CD nanozymes are enhanced by the construction of Z-scheme heterojunctions owing to the accelerated carrier transfer process. More importantly, the introduction of mild hyperthermia can further improve the peroxidase-mimic and catalase-mimic activities as well as the glGSH depletion abilities of CD@Nb2 C nanozymes, thereby producing more ROS to efficiently inhibit tumor growth. The combined therapy effect of CD@Nb2 C nanozymes through mild NIR-II photothermal-enhanced nanocatalytic therapy can achieve complete tumor eradication. This work highlights the efficient tumor therapy potential of heterojunction nanozymes.
Antiandrogen Treatment vs Active Surveillance for Patients With Prostate Cancer
Authors: Aditya N. Halthore, Gerald L. Andriole, Michael Goldstein
Journal: JAMA Oncology (2022)

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Change of Article Status to Open Access
Authors: Manali Patel, Kristopher Kapphahn
Journal: JAMA Oncology (2022)

Diana R. Withrow, PhD; Harald Anderson, PhD; Gregory T. Armstrong, MD; Michael Hawkins, DPhil; Neige Journy, PhD; Joseph P. Neglia, MD; Florent de Vathaire, PhD; Margaret A. Tucker, MD; Peter D. Inskip, ScD; Alina V. Brenner, PhD; Marilyn A. Stovall, PhD; Ibrahima Diallo, PhD; Amy Berrington de Gonzalez, DPhil; Lene H. S. Veiga, PhD
Preventive strategy for nonalcoholic fatty liver disease-related hepatocellular carcinoma
Authors: Yuri Cho, Bo Hyun Kim, Joong-Won Park
Journal: Clinical and Molecular Hepatology (2022)

The incidence of hepatocellular carcinoma (HCC) associated with nonalcoholic fatty liver disease (NAFLD) has been increasing worldwide, including Asia. Most patients with NAFLD-related HCC are at a much-advanced stage and older age at the time of diagnosis than those with virus-related HCC because they have not undergone HCC surveillance. This review provides an overview of the mechanism of hepatocarcinogenesis in NAFLD, preventive strategies for NAFLDrelated HCC, and strategies for the surveillance of patients with NAFLD.
Dysregulated Lipid Synthesis by Oncogenic IDH1 Mutation Is a Targetable Synthetic Lethal Vulnerability
Authors: Daniel Thomas, Manhong Wu, Yusuke Nakauchi, Ming Zheng, Chloe A.L. Thompson-Peach, Kelly Lim, Niklas Landberg, Thomas Köhnke, Nirmal Robinson, Satinder Kaur, Monika Kutyna, Melissa Stafford, Devendra Hiwase, Andreas Reinisch, Gary Peltz, Ravindra Majeti
Journal: Cancer Discovery (2022)

Abstract Isocitrate dehydrogenase 1 and 2 (IDH) are mutated in multiple cancers and drive production of (R)-2-hydroxyglutarate (2HG). We identified a lipid synthesis enzyme [acetyl CoA carboxylase 1 (ACC1)] as a synthetic lethal target in mutant IDH1 (mIDH1), but not mIDH2, cancers. Here, we analyzed the metabolome of primary acute myeloid leukemia (AML) blasts and identified an mIDH1-specific reduction in fatty acids. mIDH1 also induced a switch to b-oxidation indicating reprogramming of metabolism toward a reliance on fatty acids. Compared with mIDH2, mIDH1 AML displayed depletion of NADPH with defective reductive carboxylation that was not rescued by the mIDH1-specific inhibitor ivosidenib. In xenograft models, a lipid-free diet markedly slowed the growth of mIDH1 AML, but not healthy CD34+ hematopoietic stem/progenitor cells or mIDH2 AML. Genetic and pharmacologic targeting of ACC1 resulted in the growth inhibition of mIDH1 cancers not reversible by ivosidenib. Critically, the pharmacologic targeting of ACC1 improved the sensitivity of mIDH1 AML to venetoclax. Significance: Oncogenic mutations in both IDH1 and IDH2 produce 2-hydroxyglutarate and are generally considered equivalent in terms of pathogenesis and targeting. Using comprehensive metabolomic analysis, we demonstrate unexpected metabolic differences in fatty acid metabolism between mutant IDH1 and IDH2 in patient samples with targetable metabolic interventions. See related commentary by Robinson and Levine, p. 266. This article is highlighted in the In This Issue feature, p. 247
ATM Regulates Differentiation of Myofibroblastic Cancer-Associated Fibroblasts and Can Be Targeted to Overcome Immunotherapy Resistance
Authors: Massimiliano Mellone, Klaudia Piotrowska, Giulia Venturi, Lija James, Aleksandra Bzura, Maria A. Lopez, Sonya James, Chuan Wang, Matthew J. Ellis, Christopher J. Hanley, Josephine F. Buckingham, Kerry L. Cox, Gareth Hughes, Viia Valge-Archer, Emma V. King, Stephen A. Beers, Vincent Jaquet, George D.D. Jones, Natalia Savelyeva, Emre Sayan, Jason L. Parsons, Stephen Durant, Gareth J. Thomas
Journal: Cancer Research (2022)

Abstract Myofibroblastic cancer-associated fibroblast (myoCAF)–rich tumors generally contain few T cells and respond poorly to immune-checkpoint blockade. Although myoCAFs are associated with poor outcome in most solid tumors, the molecular mechanisms regulating myoCAF accumulation remain unclear, limiting the potential for therapeutic intervention. Here, we identify ataxia-telangiectasia mutated (ATM) as a central regulator of the myoCAF phenotype. Differentiating myofibroblasts in vitro and myoCAFs cultured ex vivo display activated ATM signaling, and targeting ATM genetically or pharmacologically could suppress and reverse differentiation. ATM activation was regulated by the reactive oxygen species–producing enzyme NOX4, both through DNA damage and increased oxidative stress. Targeting fibroblast ATM in vivo suppressed myoCAF-rich tumor growth, promoted intratumoral CD8 T-cell infiltration, and potentiated the response to anti–PD-1 blockade and antitumor vaccination. This work identifies a novel pathway regulating myoCAF differentiation and provides a rationale for using ATM inhibitors to overcome CAF-mediated immunotherapy resistance. Significance: ATM signaling supports the differentiation of myoCAFs to suppress T-cell infiltration and antitumor immunity, supporting the potential clinical use of ATM inhibitors in combination with checkpoint inhibition in myoCAF-rich, immune-cold tumors.
Extracellular matrix degrading enzyme with stroma-targeting peptides enhance the penetration of liposomes into tumors
Authors: Mayumi Ikeda-Imafuku, Yongsheng Gao, Suyog Shaha, Lily Li-Wen Wang, Kyung Soo Park, Mayuka Nakajima, Omokolade Adebowale, Samir Mitragotri
Journal: Journal of Controlled Release (2022)
MEX3A Mediates p53 Degradation to Suppress Ferroptosis and Facilitate Ovarian Cancer Tumorigenesis
Authors: Cheng-Kai Wang, Tzu-Jou Chen, Grace Y.T. Tan, Fang-Pei Chang, Samyuktha Sridharan, Chen-Hsin Albert Yu, Yen-Hou Chang, Yi-Jen Chen, Li-Tzu Cheng, Wendy W. Hwang-Verslues
Journal: Cancer Research (2022)

Abstract Epithelial ovarian cancer is a highly heterogeneous and malignant female cancer with an overall low survival rate. Mutations in p53 are prevalent in the major ovarian cancer histotype, high-grade serous ovarian carcinoma (HGSOC), while p53 mutations are much less frequent in other ovarian cancer subtypes, particularly in ovarian clear cell carcinoma (OCCC). Advanced stage OCCC with wild-type (WT) p53 has a worse prognosis and increased drug resistance, metastasis, and recurrence than HGSOC. The mechanisms responsible for driving the aggressiveness of WT p53-expressing ovarian cancer remain poorly understood. Here, we found that upregulation of MEX3A, a dual-function protein containing a RING finger domain and an RNA-binding domain, was critical for tumorigenesis in WT p53-expressing ovarian cancer. MEX3A overexpression enhanced the growth and clonogenicity of OCCC cell lines. In contrast, depletion of MEX3A in OCCC cells, as well as ovarian teratocarcinoma cells, reduced cell survival and proliferative ability. MEX3A depletion also inhibited tumor growth and prolonged survival in orthotopic xenograft models. MEX3A depletion did not alter p53 mRNA level but did increase p53 protein stability. MEX3A-mediated p53 protein degradation was crucial to suppress ferroptosis and enhance tumorigenesis. Consistently, p53 knockdown reversed the effects of MEX3A depletion. Together, our observations identified MEX3A as an important oncogenic factor promoting tumorigenesis in ovarian cancer cells expressing WT p53. Significance: Degradation of p53 mediated by MEX3A drives ovarian cancer growth by circumventing p53 tumor suppressive functions, suggesting targeting MEX3A as a potential strategy for treating of ovarian cancer expressing WT p53.